Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study

Susan L Samson, Feng Gu, Ulla Feldt-Rasmussen, Shaoling Zhang, Yerong Yu, Przemysław Witek, Pramila Kalra, Alberto M Pedroncelli, Philippe Pultar, Nadine Jabbour, Michaela Paul, Marek Bolanowski, Susan L Samson, Feng Gu, Ulla Feldt-Rasmussen, Shaoling Zhang, Yerong Yu, Przemysław Witek, Pramila Kalra, Alberto M Pedroncelli, Philippe Pultar, Nadine Jabbour, Michaela Paul, Marek Bolanowski

Abstract

Purpose: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Keywords: Acromegaly; Cushing’s; Hyperglycemia; Incretin-based therapy; Insulin; Pasireotide.

Conflict of interest statement

SS: Advisor for Novartis, Corcept, Chiasma. UF-R: Lecture fees from Novartis, Ipsen, Novo Nordisk, Pfizer. PW: Lecture fees from Novartis, Ipsen, Pfizer, Sanofi-Aventis, Elli-Lilly, Boehringer Ingelheim. PK: Participated in advisory board meetings of Novo Nordisk, Novartis, Eli Lilly. AMP, PP, NJ, MP: Employees of Novartis Pharmaceuticals Corporation/Novartis Pharma AG. MB: Lecture fees from Ipsen, Pfizer, Novartis. FG, SZ, YY: Nothing to disclose.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. *Patients initiated metformin upon experiencing SMBG ≥ 126 mg/dL on three consecutive days; patients who could not tolerate metformin or had a contraindication to metformin were randomized immediately; †Patients could continue permitted OADs (other than incretin-based therapies) at the discretion of the investigator; ‡Randomization stratified by disease (Cushing’s disease or acromegaly) and baseline glycemic status (HbA1c < 7% or ≥ 7%)
Fig. 2
Fig. 2
Patient disposition flowchart. *Antidiabetic treatment during the extension phase was based on investigator discretion and may have been different to the treatment received during the core phase
Fig. 3
Fig. 3
Mean ± SEM A HbA1c and B FPG levels from randomization to the end of the core study by randomized treatment, and C HbA1c and D FPG levels from study entry to end of core study by non-randomized treatment, for patients with acromegaly. n refers to the number of patients who contributed to the mean; dashed line is at HbA1c 6.5% in A and C and at FPG 126 mg/dL in B and D. SEM, standard error of the mean
Fig. 4
Fig. 4
Mean ± SEM A HbA1c and B FPG levels from randomization to the end of the core study by randomized treatment, and C HbA1c and D FPG levels from study entry to end of core study by non-randomized treatment, for patients with Cushing’s disease. n refers to the number of patients who contributed to the mean; dashed line is at HbA1c 6.5% in A and C and at FPG 126 mg/dL in B and D

References

    1. Sanno N, Teramoto A, Osamura RY, Horvath E, Kovacs K, Lloyd RV, Scheithauer BW. Pathology of pituitary tumors. Neurosurg Clin N Am. 2003;14(1):25–39. doi: 10.1016/S1042-3680(02)00035-9.
    1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015;386(9996):913–927. doi: 10.1016/S0140-6736(14)61375-1.
    1. Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab. 2011;96(3):632–642. doi: 10.1210/jc.2010-1942.
    1. Gadelha MR, Kasuki L, Lim DST, Fleseriu M. Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocr Rev. 2019;40(1):268–332. doi: 10.1210/er.2018-00115.
    1. Scaroni C, Zilio M, Foti M, Boscaro M. Glucose metabolism abnormalities in Cushing syndrome: from molecular basis to clinical management. Endocr Rev. 2017;38(3):189–219. doi: 10.1210/er.2016-1105.
    1. Alexopoulou O, Bex M, Kamenicky P, Mvoula AB, Chanson P, Maiter D. Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary. 2014;17(1):81–89. doi: 10.1007/s11102-013-0471-7.
    1. Colao A, Bronstein MD, Freda P, Gu F, Shen CC, Gadelha M, Fleseriu M, van der Lely AJ, Farrall AJ, Hermosillo Resendiz K, Ruffin M, Chen Y, Sheppard M. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791–799. doi: 10.1210/jc.2013-2480.
    1. Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, Pronin V, Raverot G, Shimon I, Lievre KK, Fleck J, Aout M, Pedroncelli AM, Colao A. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, Phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875–884. doi: 10.1016/S2213-8587(14)70169-X.
    1. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM, Pasireotide B2305 Study Group (2012) A 12-month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 366(10):914–924
    1. Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, Boscaro M, Salvatori R, Yamada M, Tauchmanova L, Roughton M, Ravichandran S, Petersenn S, Biller BMK, Newell-Price J. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 2018;6(1):17–26. doi: 10.1016/S2213-8587(17)30326-1.
    1. Highlights of prescribing information SIGNIFOR® (pasireotide) injection, for subcutaneous use (2020). . Accessed 30 June 2021
    1. Highlights of prescribing information SIGNIFOR® LAR (pasireotide) for injectable, for intramuscular use (2019). . Accessed 30 June 2021
    1. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002;146(5):707–716. doi: 10.1530/eje.0.1460707.
    1. Batista DL, Zhang X, Gejman R, Ansell PJ, Zhou Y, Johnson SA, Swearingen B, Hedley-Whyte ET, Stratakis CA, Klibanski A. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab. 2006;91(11):4482–4488. doi: 10.1210/jc.2006-1245.
    1. Hofland LJ, van der Hoek J, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, de Herder WW, Beckers A, Lamberts SW. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol. 2005;152(4):645–654. doi: 10.1530/eje.1.01876.
    1. Hofland LJ, van der Hoek J, van Koetsveld PM, de Herder WW, Waaijers M, Sprij-Mooij D, Bruns C, Weckbecker G, Feelders R, van der Lely AJ, Beckers A, Lamberts SW. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab. 2004;89(4):1577–1585. doi: 10.1210/jc.2003-031344.
    1. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446–3453. doi: 10.1210/jc.2013-1771.
    1. Kumar N, Shah NL. Pasireotide-induced hyperglycemia. MOJ Clin Med Case Rep. 2017;6(2):45–46.
    1. Sheppard M, Bronstein MD, Freda P, Serri O, De Marinis L, Naves L, Rozhinskaya L, Hermosillo Resendiz K, Ruffin M, Chen Y, Colao A. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study. Pituitary. 2015;18(3):385–394. doi: 10.1007/s11102-014-0585-6.
    1. Breitschaft A, Hu K, Hermosillo Resendiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458–465. doi: 10.1016/j.diabres.2013.12.011.
    1. Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly. Pituitary. 2016;19(5):536–543. doi: 10.1007/s11102-016-0734-1.
    1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care. 2012;35(6):1364–1379. doi: 10.2337/dc12-0413.
    1. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF. Managing hyperglycemia in patients with Cushing's disease treated with pasireotide: medical expert recommendations. Pituitary. 2014;17(2):180–186. doi: 10.1007/s11102-013-0483-3.
    1. Coopmans EC, Muhammad A, van der Lely AJ, Janssen J, Neggers S. How to position pasireotide LAR treatment in acromegaly. J Clin Endocrinol Metab. 2019;104(6):1978–1988. doi: 10.1210/jc.2018-01979.
    1. American Diabetes Association 6. Glycemic targets: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S61–S70. doi: 10.2337/dc19-S006.
    1. Nauck MA, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care. 2009;32(Suppl 2):S223–S231. doi: 10.2337/dc09-S315.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren